The Regulation of Dietary Supplements Marketed for “Cosmetic Neurocognitive Enhancement”

Overview of Dietary Supplement Regulations

Currently, dietary supplements are regulated similarly to food under the Dietary Supplement Health and Education Act (DHSEA). The DHSEA defines dietary supplements as a “vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient mentioned above.” Where pharmaceutical drugs generally require years of pre-market research, dietary supplements can immediately enter the market without years of extensive premarket research.  The Food and Drug Administration (FDA) can pull the dietary supplements from the market “only after repeated instances of adverse reactions,” which makes it reliant on consumers, medical providers, and manufacturers to report adverse events post market. The DSHEA, therefore, imposes more responsibility on the manufacturer rather than on the regulators for ensuring consumers are protected and not misled by the marketing of dietary supplements.

However, the DSHEA raises three major questions:

1. Are there essential differences between pharmaceuticals and supplements?
2. If so, do these differences justify the radically different approach under which drugs and supplements are regulated today?
3. To what extent should the government regulate any substance used to treat, ameliorate, or prevent disease?

As mentioned above, there is no requirement of pre-market research before dietary supplements enter the market. Both the FDA and the Federal Trade Commission (FTC) share jurisdiction over the labeling of dietary supplements. The FDA also has a role in determining if a dietary supplement should be pulled from the market due to safety concerns.

The Role of the FDA in Dietary Supplement Labeling

Federal law requires that all dietary supplements must be labeled “Dietary Supplements.” Certain statements are allowed that describe the structure or function of the dietary supplement but do not address the treatment of a disease (a health claim). The FDA does not have to preapprove the labeling before it makes it to the market. Manufacturers are only required to notify the FDA within 30 days of the first use of any claim and must include a disclaimer that the FDA has not evaluated the claim and the product is not intended to “diagnose, treat, cure or prevent any disease.” The FDA has historically tracked down companies that violate rules regarding labeling. The DSHEA and the Federal Food, Drug, and Cosmetic (FD&C) Act prohibit companies from claiming that a dietary supplement can cure, treat, or prevent specific diseases.

Under the Nutritional Labeling and Education Act of 1990 (NLEA), the FDA is empowered to “issue regulations providing for the use of statements that describe the relationship between a substance and a disease (‘health claims’) in the labeling of foods and dietary supplements.” In order for a supplement manufacturer to be able to make a health claim about a dietary supplement, the FDA must review the scientific information and make a determination of whether there is significant scientific agreement (SSA). Therefore, while the DSHEA allows immediate entry of dietary supplements into the market, the NLEA requires FDA review for scientific consensus if the manufacturer is making a health claim. However, under DSHEA, this review may occur after the product has already hit shelves.

To make a determination, the agency considers publicly available and written information regarding the relationship between the substance and a disease. Moreover, studies must be submitted in the petitions seeking claims. Typically, the FDA requires interventional and observational studies so they can evaluate the study design, execution, and analyses to determine if the studies were scientifically sound. There are guidelines or requirements for each type of study reviewed that must be evaluated. The FDA also considers viewpoints of qualified third-party experts, so long as that evaluation is available publicly. If the evidence does not meet the SSA standard, then the claim “should include qualifying language that identifies the limits to the level of scientific evidence to support the relationship.

The Role of the FDA in Regulating the Safety of Dietary Supplements

The lack of a requirement for pre-market approval of dietary supplements poses issues for the FDA in regulating the safety of dietary supplements. Lack of pre-market research and testing pertaining to safety introduces challenges in determining if the supplement is the cause of an adverse event, defined simply as “any health-related event associated with the use of a dietary supplement that is adverse.”

Dietary supplement companies are required to report serious adverse events associated with their supplements to the FDA. A serious adverse event is defined as an adverse event that:

• Results in death, a life-threatening illness, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital birth defect; or
• Requires medical intervention to prevent one of these outcomes.

The FDA provides guidance on how to submit the serious adverse event report. Typically, serious adverse events are submitted via a MedWatch Form (also known as Form FDA 3500A), which can be submitted electronically as of September 2013. The report must be submitted within 15 business days of the responsible person (e.g., manufacturer, packer, or distributor) receiving the information. The manufacturer must include, at minimum, the following information in the serious adverse event report:

• An identifiable patient
• An identifiable initial reporter
• Identity and contact information for the person responsible (i.e., the manufacturer, packer, or distributor submitting the serious adverse event report to the FDA)
• A suspect dietary supplement
• A serious adverse event or fatal outcome

“Cosmetic Neurocognitive Enhancement” and Its Overlap with Cognitive Domains Affected in Neurological Disorders and Other Conditions

Our society “demands increasingly high performance levels (e.g., study grades or work projects), ideally with the least amount of time necessary.” One physician scholar defined cosmetic neurocognitive enhancement as involving the use “prescription stimulant drugs to enhance cognitive function such as attention, concentration, and memory beyond normal limits in healthy people.” However, cognitive enhancement is far more broad in that “[a] variety of means can be used to enhance performance ranging from pharmaceutical cognitive enhancers (‘PCEs’) (‘smart drugs’) to brain stimulation techniques and smart glasses.”

Unlike cosmetic surgery, which has physically and objectively measurable outcomes, the effectiveness of “cosmetic neurocognitive enhancement” can only be measured on individuals’ past experience. Additionally, while cosmetic surgery carries a one-time greater risk than the use of prescription drugs, it is unclear what the effects are of the chronic use of drugs or substances such as stimulants. The brain is not well understood, is highly interconnected, and therefore, there may be a wide variety of side effects such as those known for stimulants: “mood changes, irritability, anxiety, impulsivity, and problems with reality testing.” Moreover, the brain is difficult to target pharmaceutically due to the blood-brain barrier (BBB)—a delicate membrane generated by endothelial cells that makes up the inside layer of cerebral micro vessels that separates the brain parenchyma from systemic circulation. It, therefore, regulates the entrance of blood plasma components, red blood cells, and leukocytes (white blood cells) into the central nervous system. In fact, the BBB makes it challenging to identify an appropriate dose to target brain structures.

Moreover, the cognitive domains implicated in neurological disorders such as dementia or Alzheimer’s overlap with the domains that healthy individuals may seek to enhance. For example, people with dementia can exhibit problems with “memory, attention, communication, reasoning, judgment, problem solving, and visual perception beyond typical age-related changes in vision.” Cognitive impairment can also be a symptom of other disorders and conditions such as stroke, traumatic brain injury, and developmental disabilities. Some common signs of cognitive impairment are memory loss, failure to recognize familiar people and places, trouble exercising judgments, changes in mood and behavior, vision problems, and difficulty planning and carrying out tasks. These products (supplements and “natural” products) are also directly advertised to patients or caregivers of patients with neurological disorders for the purposes of preventing such disorders. Thus, the very same dietary supplements that might be taken to enhance brain function in healthy individuals might also conceivably be utilized in individuals with recovering from stroke and traumatic brain injuries and experiencing dementia.

The overlap between the two contexts for using dietary supplements presents a challenge for the determination of whether the manufacturers are making health claims when they market their products as neurocognitive enhancers. The immediate and more narrow implication is that if such claims are health claims, then the manufacturer would need to apply to the FDA for approval with relevant and sufficient research to make such claims. On a broader level, the implication is that perhaps systematic pre-market research should be required prior to market entry, at least for certain dietary supplements making specific claims such as improving a specific area of the brain or areas of cognition. Below are examples of claims that could meet the requirement for premarket research:

• Thorne – Brain Factors: makes claims such as: “Help your brain reach full potential by promoting cognitive, learning, and memory function” and “promotes growth of brain and nerve cells,… increasing NAD+, which enhances cellular energy production.”
• NeuroQ: includes claims of including “key ingredients for enhancing memory and focus” and that the “memory and focus ingredients work synergistically to protect long-term brain health, increase blood flow, clear toxins, and support healthy brain cells.”
• Mind-Lab-Pro: includes claim that one ingredient, Citicoline “boost[s] neural regeneration, brain energy, attention, focus, memory, and more.”

Dietary Supplements, “Cosmetic Neurocognitive Enhancement,” and Cognitive Impairment

The following examples of cognitive health supplements are not exhaustive. The National Institutes of Health (NIH) published an article in 2012 listing eight types of commonly used supplements for cognitive health: gingko biloba, B vitamins (B6, B9, and B12), vitamin E, w-3 fatty acids, vitamins A and C, vitamin D, phospholipids (phosphatidylserine and phosphatidylcholine), and ginseng. In late 2019, WebMD advertised “Brain Supplements That Do and Don’t Work” including: B vitamins (do), caffeine (don’t), L-theanine (do), Omega-3s (do), vitamin E (may be helpful), ginkgo biloba (don’t), ginseng (don’t), curcumin (found in turmeric and an ingredient in curry powder, needs more research), and CDP-choline (sold as a prescription in Europe rather than a dietary supplement, maybe helpful in older people). Other websites such as consumerhealth.org have similar articles with advertisements for dietary supplements marketed for brain health and enhancement. Many of these aforementioned supplements have been studied by various researchers pertaining to their use in both healthy individuals and patients at risk for or currently experiencing cognitive impairment. However, these studies are inconsistent in their sample sizes, safety assessments, and administration of the supplements, which raises challenges to interpreting a causal relationship between the substance and any benefits.

Efficacy of Dietary Supplements

Since dietary supplements are not subject to pre-market testing, not much is known about their efficacy. Though the research on dietary supplements for “cosmetic neurocognitive enhancement” in healthy populations is limited, there has been research conducted in the use of nutrition and dietary supplements in neurological disorders such as Alzheimer’s disease (and other similar disorders). Moreover, there is research into nutritional interventions to slow down or ease the process of aging and its effects on overall health. This research may inform the need for greater testing of dietary supplements for efficacy and safety prior to entry into the market.

Dietary Supplement and Nutrition Research in Alzheimer’s and Related Disorders

The efficacy of dietary supplements and nutritional interventions have been studied in mild cognitive impairment (MCI), Alzheimer’s disease, prodromal AD, preclinical AD, unspecified dementia and vascular dementia. Solfrizzi, et al., conducted a systematic review of 32 observational studies, involving patients aged 60 and older, that were published 2014–2017. The studies reviewed showed a variety of responses to the dietary supplements in various cognitive domains. In some studies, the patients in the supplement arm of the study experienced cognitive decline. In the studies where the results indicated benefits from use of dietary supplements, the benefits varied on which cognitive domain improved (such as memory versus verbal fluency).

Dr. Lai Kuan Lee and her team studied the efficacy and safety of docosahexaenoic acid-concentrated fish oil supplementation in patients with MCI. This trial implemented a 12-month, randomized, double-blind, placebo-controlled design. The fish oil group of patients showed statistically significant improvement in short-term and working memory, immediate verbal memory, and delayed recall. The fish oil group also showed improvement in memory change as compared to patients receiving the placebo. Both groups tolerated the supplement and side effects were minimal. Overall, the study indicated a potential benefit in slowing down cognitive decline in patients with MCI.

In its 2012 article, the NIH conducted a review of studies that examined that potential benefits of supplementation with dietary supplements to prevent or ameliorate cognitive decline, dementia, and Alzheimer’s disease. The NIH’s general conclusions were that the studies were small and limited and therefore prone to bias and chance. Many of the studies were observational, and therefore, causal relationships could not be extrapolated from the data. It is possible that these studies found potential benefits to preventing or ameliorating cognitive decline, but the extensive clinical trials would be needed for the purposes of determining efficacy.

The studies cited in the reviews above highlight the importance of rigorous testing of substances that are aimed at treating a neurological disorder. As noted above, the variety of responses to various dietary supplements indicate that not all dietary supplements may be useful in treating neurological disorders. It may be fair to conclude that if a supplement provides no benefit for treating a neurological disorder, there is unlikely a benefit in enhancing cognition in healthy individuals. On the flip side, it is arguable that just because a dietary supplement was shown to be ineffective to treat a certain neurological disorder does not mean that they lack benefit in improving brain health and function overall. Neither argument has ground until there has been extensive clinical testing.

Dietary Supplements for Neurocognitive Enhancement in Healthy Individuals

The rate of dietary supplement consumption among younger people is increasing. Some studies do suggest that the dietary supplements may modulate some aspects of cognitive performance in healthy young adults. Pomeroy, et al., conducted a systematic review of supplement use in young adults and military personnel. The supplements investigated were: beta-alanine, caffeine, flavonoids, ginkgo biloba, ginseng, guarana, nitrate, omega-3s, pre-biotics, tyrosine, and B vitamins. The sample sizes varied greatly between studies with as few as 11 to more than 200 participants.

Overall, the studies did seem to show some potential cognitive enhancement from healthy young people. Some positive effects included processing speed, improved memory, attention, and executive functioning. However, not a single supplement showed a benefit for all areas of cognitive functioning nor did any supplements improve all areas of a single cognitive domain. Overall, the effects and results were inconsistent and the studies varied on whether they were giving the participants the pure form of the supplement or the supplement mixed with other ingredients that could be affecting the study participants.

Safety of Dietary Supplements

One of the biggest issues regarding the safety of dietary supplements is that they are not subject to rigorous pre-market testing like drugs are. Essentially, there is little to no data or information regarding the safety of a food product before it goes to the market. For example, the studies reviewed by Pomeroy, et al., generally did not assess or report adverse events, with only one study reporting paresthesia (tingling) as a physical side effect for inappropriate administration of the supplement.

Dietary supplement manufacturers must list the serving size and the number of servings per container, declare each dietary ingredient in the product, and except for dietary ingredients that are proprietary blend, provide information on the amount of the dietary ingredient per serving. Therefore, the exact contents of supplements may not be disclosed on the label. The ingredients included in the supplements may not be considered a dietary substance. For example, NeuroScience Solutions, Inc., received a warning letter from the FDA regarding Kavinace, which included an ingredient, phenibut, that did not meet the criteria under 201(ff)(1) of the FD&C Act to be considered a dietary ingredient.

A major issue in the dietary supplement industry is the “incorporation of undisclosed pharmaceuticals into dietary supplements.” Pharmaceuticals are subject to pre-market testing and are considered drugs, which means that the manufacturers who include them in supplements are violating federal law. Moreover, some of the included pharmaceuticals have been deemed unsafe and ineffective.

A 2015 study found that dietary supplement adverse effects made up an average of 23,000 emergency department visits per year. Ginkgo biloba may be associated with harms caused by drug interactions, with one study showing that it may interact with antiplatelet or anticoagulant medications, therefore increasing likelihood of bleeding or hemorrhagic stroke. Other studies have reported that adverse events can include increased risk of bleeding (gingko biloba, fish oil), liver damage (unspecified supplements), interactions with ibuprofen (gingko biloba), and death (caffeine and energy supplements).

Consumer Concerns

The dietary supplement industry is highly prevalent in our society. Within the first ten years after the passage of the DSHEA, the dietary supplement industry had quadrupled, and the growth has continued since. In 2016, the industry employed more than 750,000 people. Moreover, between 2017–2019, the industry was worth $122 billion and was a $30 billion per year endeavor. The incredible growth of the industry underscores consumers’ great interest in buying and using dietary supplements .

Direct-to-consumer advertising (DTCA) is concerning in relation to dietary supplements. DTCA “refers to a variety of marketing practices based on a combination of information and promotion strategies directed at consumers through different media such as radio and television broadcasts, newspaper and magazine ads, and more recently, through the Internet.” DTCA, specifically on the internet, has had a substantial impact on the practice of psychiatry and neurology in that physicians are being asked to prescribe more specific medications even prior to patients receiving a diagnosis. Moreover, the regulations for DTCA apply expressly to prescription drugs but no other products such as dietary supplements.

The implications are that every day, consumers may be easily exploited by the dietary supplement industry. Consumers tend to trust untested supplements more than drugs even though drugs are tested for safety and efficacy. It may be that that consumers do not trust pharmaceutical companies or that they equate claims of being “natural” with being safe.And since dietary supplements are not required to undergo extensive pre-market testing, they are often of lower cost and therefore are appealing to consumers due to low price along with their promises of ameliorating or preventing health conditions. Some of the most vulnerable individuals may be those living in poverty, the elderly, and adolescents.

Many older adults believe that maintaining cognitive health is the key to aging well. Almost half of adults report using complementary and alternative medicine (CAM)—which includes dietary supplements—for cognitive health. Approximately 52% of older adult prescription users concurrently use dietary supplements. Another study found similarly that nearly one-half of older adults regularly use OTC medications or dietary supplements. In the survey, more than half of older adults used five or more prescription medications, OTC medications, or dietary supplements, with some even reporting using five or more dietary supplements.

The FDA Should Regulate Dietary Supplements that Make Claims of Cosmetic Neurocognitive Enhancement

The current regulatory framework is not sufficient for addressing the efficacy and safety concerns for dietary supplements marketed as neurocognitive enhancers. Scholars have called for increased regulation of dietary supplements citing three main issues: (1) lack of disclosure of all the ingredients included in a given dietary supplement, (2) lack of clarity on what makes a health claim made by the seller of the supplement, and (3) safety and efficacy concerns pertaining to dietary supplements. One scholar claims that the DSHEA precludes adequate evaluation of dietary supplements for safety and efficacy and should therefore be repealed. There is little safety and efficacy information for dietary supplements because they are regulated as food. However, there is some evidence that consumers have experienced adverse effects similar to those of over-the-counter (OTC) and prescription medications. Depending on the product and the claims made by the manufacturer of the product, there may be need to investigate the product through the clinical trial process. However, a strict regulation imposing clinical trials on all dietary supplements may not be warranted, depending on the factors such as: (1) whether the claims made by the manufacturers are considered health claims and (2) whether there is need for safety and efficacy data prior to market entry.

The FDA should have greater regulatory control over dietary supplements before entry into market. However, strict adherence to the drug/clinical trial regulatory framework for dietary supplements may not be feasible, practical, or warranted. The clinical trials process is slow and costly. The following proposals are not mutually exclusive but may be considered as separate options as well.

“Cosmetic Neurocognitive Enhancement” Claims Should be Considered Health Claims

As mentioned earlier in this paper, there is significant and almost identical overlap between the cognitive domains for which healthy individuals seek enhancement and the cognitive domains affected in neurological conditions and other medical conditions. Furthermore, this overlap extends to the substances that are being investigated. Many of the same supplements that have been investigated for cognitive enhancement have also been investigated for ameliorating or preventing cognitive impairment in neurological conditions such as Alzheimer’s disease. Given the aforementioned and the complexity of the brain, any claim a seller or manufacturer of a supplement makes about cognitive domain should be held to the same scrutiny as any other health claim. This will facilitate more systematic and standardized research across the board, so that more solid conclusions can be drawn about the safety and efficacy of neurocognitive-enhancing supplements.

One issue with this approach is that the research on supplements and nutritional interventions regarding cognitive enhancement, prevention of cognitive impairment, and ameliorating cognitive impairment may not meet the research requirements set forth by the FDA. Another issue is that manufacturers may decide to instead remove the specific claims and make general claims such as “good for brain health” so that they can push their products to the market without any regulatory stop gates.

Amend the DSHEA to Grant FDA More Regulatory Control Over Dietary Supplements That Are Marketed with Health Claims

Because the primary burden it places is on manufacturers to report adverse incidents, and only after the supplement has come to market, the DSHEA as it exists today makes it difficult to incorporate scientific investigation of the efficacy and safety of dietary supplements. The NLEA empowers the FDA to evaluate scientific consensus regarding health claims made by manufacturers regarding their dietary supplements. However, these supplements may make it to market prior to being evaluated. Therefore, the DSHEA should be amended in such a manner as to allow the FDA to require pre-market research on dietary supplements on a case-by-case basis. Prior to market entry of any supplement, manufacturers should be required to submit a comprehensive ingredient list and the intended uses and intended marketing for the supplements. If there is any research that meets FDA requirements for health claim evaluation, that should be submitted as well. The FDA can then review this information and decide if a larger clinical trial is needed prior to market entry.

Barring any adjustments due to COVID-19, the investigation of a drug or a vaccine traditionally occurs in phases. Historically, the FDA reviewed clinical trial data in the form of a formal new drug application (NDA) after the results of the Phase III trial had been analyzed. Phase I clinical trials typically investigate safety and determine dosage ranges. These trials are typically short-term, only running for about three to six months. According to the FDA, only about 70% of drugs move on to the next phase. Phase II trials investigate the efficacy and safety of the drug or vaccine in the target patient population, and typically run from several months to approximately two years.  The sample size is increased as compared to Phase I. Approximately 33% of drugs move on from Phase II clinical trials. Phase III clinical trials continue investigating efficacy and monitoring of safety concerns.  These trials typically are investigating the efficacy of treatment in comparison with available standards of care. These trials typically run for about one to four years and have larger sample sizes.  Only approximately 25–30% of drugs move on from Phase III clinical trial. Drug approval or disapproval usually takes place after reviewing the results of the Phase III trial. Recently, the FDA has implemented Phase IV trials after the drug has been approved, to monitor safety and efficacy of drugs due to the concern about long-term safety effects of drugs that are approved by the FDA.

Section 505(o)(3) of the Food and Drug Administration Amendments Act (FDAAA) authorizes the FDA to require post-marketing studies or clinical trials (essentially Phase IV trials) at the time or after approval if the FDA becomes aware of new safety information. According to section 505-1(b)(3) of the Act, new safety information includes data about serious risk or unexpected risk that is associated with the use of the drug.  Even if the risk is known at the time of approval of the drug, more may be learned after approval about its frequency or severity that can be considered new safety information. Post-marketing studies and clinical trials may be required for any or all the following three purposes:

• To assess a known serious risk related to the use of the drug.
• To assess signals of serious risk related to the use of the drug.
• To identify an unexpected serious risk when available data indicates the potential for a serious risk.

The FDAAA defines clinical trials and studies as follows:

• Clinical trials are any prospective investigations in which the applicant or investigator determines the method of assigning the drug product(s) or other interventions to one or more human subjects. 
• Studies are all other investigations, such as investigations with humans that are not clinical trials as defined above (e.g., observational epidemiologic studies), animal studies and laboratory experiments.

The FDA would not impose the traditional clinical trial process but rather allow manufacturers to conduct hybrid clinical trials with a dose escalation/determination phase and a limited participant sample size. Once safe doses have been determined, the manufacturer can expand to a larger clinical trial that could be considered an equivalent to the Phase III step of research. Safety reporting requirements would remain the same. Manufacturers would only need to collect safety and efficacy data, no other endpoints. Once data has been collected and analyzed, the manufacturer would apply, similar to a New Drug Application (NDA), to the FDA for market approval. The FDA would then make a final determination.

The benefit of this process is that it would increase the FDA’s oversight of dietary supplements pre-market without requiring all dietary supplements to undergo pre-market research prior to FDA approval. Also, those supplements that are required to undergo pre-market research would not subject to the lengthy and costly clinical trial process that drugs undergo, rather, a separate, pre-market research process for dietary supplements would be put in place with requirements modeled after those of drugs but less stringent. The FDA could also require post-market research as needed to streamline the pre-market research to market entry process. On the other hand, arguably imposing such a process could prove onerous and have a chilling effect on the market for neuro-supplements. However, supplements that do not make any specific health claims need not undergo the arduous clinical trial process or a modified clinical trial process. Moreover, such a requirement could prevent inaccurate or misleading labeling and marketing of neurological supplements.

Conclusion

“Cosmetic neurocognitive enhancement” presents an interesting challenge to the regulation of dietary supplements in that the cognitive domains targeted overlap significantly with areas affected by cognitive impairment in neurological and other medical conditions. The main question is whether by seeking to or claiming to enhance various aspects of cognition, the dietary supplement is trying to preemptively treat cognitive decline or prevent neurological conditions. Though this may not be the express goal, it is not unreasonable to conceptualize this as an implied goal. Therefore, any claims supplement manufacturers make about enhancing a cognitive domain should be considered a health claim under the federal regulations, because of the significant and inseparable overlap between the domains for which enhancement is sought and those affected by cognitive impairment. The FDA should have more oversight over whether a dietary supplement requires pre-market research prior to market entry.